In higher organisms the formation of the steroid scaffold is catalysed exclusively by the membrane-bound oxidosqualene cyclase (OSC; lanosterol synthase). In a highly selective cyclization reaction OSC forms lanosterol with seven chiral centres starting from the linear substrate 2,3-oxidosqualene. Valuable data on the mechanism of the complex cyclization cascade have been collected during the past 50 years using suicide inhibitors, mutagenesis studies and homology modelling. Nevertheless it is still not fully understood how the enzyme catalyses the reaction. Because of the decisive role of OSC in cholesterol biosynthesis it represents a target for the discovery of novel anticholesteraemic drugs that could complement the widely used statins. Here we present two crystal structures of the human membrane protein OSC: the target protein with an inhibitor that showed cholesterol lowering in vivo opens the way for the structure-based design of new OSC inhibitors. The complex with the reaction product lanosterol gives a clear picture of the way in which the enzyme achieves product specificity in this highly exothermic cyclization reaction.
The binding structures of 11 human oxidosqualene cyclase inhibitors designed as cholesterol-lowering agents were determined for the squalene-hopene cyclase from Alicyclobacillus acidocaldarius, which is the only structurally known homologue of the human enzyme. The complexes were produced by cocrystallization, and the structures were elucidated by X-ray diffraction analyses. All inhibitors were bound in the large active center cavity. The detailed binding structures are presented and discussed in the light of the IC50 values of these 11 as well as 17 other inhibitors. They provide a consistent picture for the inhibition of the bacterial enzyme and can be used to adjust and improve homology models of the human enzyme. The detailed active center structures of the two enzymes are too different to show an IC50 correlation.
Enantiomerically pure cis-and trans-5-alkyl-l-benzoyl-2-(tert-butyl)-~~-methylimidazolidin-4-ones (1, 2, 11, 15, 16) and trans-2-(terf-butyl)-3-methyl-5-phenylimidazolidin-4-one (20). readily available from (S)-alanine, (S)-valine, (S)-methionine, and (R)-phenylglycine are deprotonated to chiral enolates (cf. 3, 4, 12, 21). Diastereoselective alkylation of these enolates to 5,5-dialkyl-or 5-alkyl-5-arylimidazolidinones (5, 6, 9, 10, 13a-d, 17, 18, 22) and hydrolysis give a-alkyl-a-amino acids such as (R)and (S)-a-methyldopa (7 and 8a, resp.), (S)-amethylvaline (14) and (R)-a-methyl-methionine (19). The configuration of the products is proved by chemical correlation and by NOE 'H-NMR measurements (see 23, 24). In the overall process, a simple, enantiomerically pure a-amino acid can be a-alkylated with retention or with inversion of configuration through pivalaldehyde acetal derivatives. Since no chiral auxiliary is required, the process is coined 'self-reproduction of a center of chirality'. The method is compared with other a-alkylations of amino acids occurring without racemization. The importance of enantiomerically pure, a-branched a-amino acids as synthetic intermediates and for the preparation of bio~ogicdl~y active compounds is discussed.In [l], we have shown that simple amino acids such as (S)-alanine, (S)-valine, (R)-phenylglycine, (S)-phenylalanine, and (S)-methionine can be converted selectively to imidazolidinones such as 1 and 2 of either cis-or trans-configuration. We now show that these imidazolidinones are deprotonated to synthetically useful chiral enolates.A) Reactions of the Chiral Imidazolidinone Enolates with Electrophiles. -As a first example, the preparation of ( R ) -or (S)-a -methyldopa ( =I 2-amino-2-methyl-3-(3,4-di-hydroxypheny1)propionic acid) from (S)-alanine is described (Scheme I). Solutions of the imidazolidinones (1 or 2) in THF were treated at dry-ice temperature with a slight excess of lithium diisopropylamide (LDA). Bright orange-red-colored solutions of the enantiomeric enolates (3, 4) were formed, which were combined with 3,4-dimethoxybenzyl bromide. Rapid decolorization indicated the progress of the alkylation step furnishing the enantiomeric 5,5-disubstituted imidazolidinones (5, 6, ca. 60 YO). We did not detect more than one diastereoisomer by HPLC of the crude products. Within experimental error, the two isomers 5 and 6 had identical physical properties such as melting points, IR, and NMR spectra, but an opposite sense of specific rotation.The heterocyclic ring and the phenolic methyl-ether groups of the enantiomer 6 were cleaved by heating for 4 hours in 6~ HC1 at 180" in a sealed tube. Isolation of the a-methyldopa thus produced caused considerable problems due to the known [2a] sen-') 2,Part of the projected Ph. D. theses of J.
New orally active non-terpenoic inhibitors of human 2,3-oxidosqualene cyclase (hOSC) are reported. The starting point for the optimization process was a set of compounds derived from a fungicide project, which in addition to showing high affinity for OSC from Candida albicans showed also high affinity for human OSC. Common structural elements of these inhibitors are an amine residue and an electrophilic carbonyl C atom embedded in a benzophenone system, which are at a distance of about 10.7 A. Considering that the keto moiety is in a potentially labile position, modifications of the substitution pattern at the benzophenone as well as annelated heteroaryl systems were explored. Our approach combined testing of the compounds first for increased binding affinity and for increased stability in vitro. Most promising compounds were then evaluated for their efficacy in lowering plasma total cholesterol (TC) and plasma low-density lipoprotein cholesterol (LDL-C) in hyperlipidemic hamsters. In this respect, the most promising compounds are the benzophenone derivative 1.fumarate and the benzo[d]isothiazol 24.fumarate, which lowered TC by 40% and 33%, respectively.
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